DUDLEY, UK—Serum uric acid (SUA) levels appear to be an independent risk factor for cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA), and patients with SUA >e;6 mg/dL had a 6-fold higher risk of CVD than those with the lowest levels, British researchers report in Rheumatology.¹

"This cross-sectional study suggests that SUA may be independently associated with CVD in RA patients. This needs to be confirmed in prospective studies," wrote lead author V. F. Panoulas, MD, with the department of rheumatology at Russells Hall Hospital in Dudley, West Midlands, UK.

Dr. Panoulas and colleagues, led by George D. Kitas, MD, PhD, FRCP, assessed all traditional CVD risk factors and SUA levels in 400 consecutive RA patients. They found that RA patients with CVD had significantly higher SUA levels than RA patients who did not have CVD, and this association remained significant after adjusting for CVD risk factors, physical function, and use of diuretics or statins.

Dr. Panoulas noted that conventional CVD risk factors such as smoking and hypertension are more prevalent in RA patients than in the general population but cannot fully explain the excess CV burden of RA patients. This observation sparked a search for unconventional risk factors.

Uric acid attracted the team's interest because it can be a mediator of endothelial dysfunction, vascular smooth cell proliferation, and low-grade inflammation, "all precursors of hypertension and CVD." There has been little study into SUA levels in RA, so the research team explored the potential association of UA and CVD in RA and estimated the levels at which SUA becomes dangerous to CV health in these patients.

Most of the patients in this study (87.5%) were on DMARDs (56.3% on methotrexate). Mean SUA levels were 5.18 mg/dL, and at baseline 37 (9.3%) patients were hyperuricemic (UA >8.41 mg/dL for males, >6.73 mg/dL for females). CVD was present at baseline in 19.5% of patients, 7% had already suffered a myocardial infarction (MI), 4.3% a stroke, 2.8% had undergone angioplasty, 3.3% coronary artery bypass grafting (CABG), and 3.3% had documented CVD.

SUA levels were 5.68 mg/dL in RA patients with CVD versus 5.06 mg/dL in RA patients without CVD (P = .001). SUA levels were higher in males than in females (6.02 mg/dL versus. 4.87 mg/dL, P <.001). CVD prevalence was 34.2% among RA patients in the highest quintile for SUA and 13.9% for those in the lowest quintile (P = .003).

"After adjusting for age, gender, hypertension, body mass index, total cholesterol, smoking pack-years, quantitative insulin sensitivity check index, health assessment questionnaire, RA disease duration, use of diuretics and statins, the association between SUA and CVD remained significant (OR = 1.36, 95% CI 1.039-1.79, P = .025," the authors report.

They conclude that RA patients in the highest quintile for SUA (>e;6.38 mg/dL) had a 3.21-fold increase in the odds of having CVD, compared with those in the lowest quintile (<3.86 mg/dL).

The authors caution that this cross-sectional, observational study "cannot provide proof of causality or independence in the associations found." They urge further investigation in prospective studies of possible pathogenic mechanisms and "potential clinical use of SUA as an early biomarker of future CVD events in this group of patients...."

Daniel H. Solomon, MD, MPH, associate professor of medicine at Harvard Medical School and chief, section of clinical sciences in the divisions of rheumatology and pharmacoepidemiology at Brigham and Women's Hospital in Boston, Massachusetts, reviewed the study for Musculoskeletal Report.

Dr. Solomon said that SUA might be clinically useful as a biomarker for CVD risk in RA patients, particularly since SUA has been shown to be a strong predictor of CVD in other studies. "We need longitudinal studies that examine serum uric acid at ‘baseline' and then follow-up patients with RA to see who develops CVD."

"Testing uric acid-lowering therapy as a means for preventing CVD is an intriguing concept, not only in the RA population. It has been tried and failed in patients with congestive heart failure (who do not have RA). Some of the complicating issues are the potential toxicity of uric acid-lowering therapy and the unknown relationship between duration of hyperuricemia and CVD. Moreover, statin therapy has been proven to be safe and effective in many patient populations at risk for CVD. Statins may be a better first therapeutic option for preventing CVD in RA. Clearly, there is a great need for randomized controlled trials of strategies to prevent CVD in patients with rheumatic disease," Dr. Solomon said.

Patrick Dessein, MD, whose group found an association between SUA and atherosclerosis in RA , told Musculoskeletal Report, "The question is if uric acid is just a marker or is directly involved in atherogenesis in RA. Investigating the effect of uric acid lowering intervention on cardiovascular disease outcomes seems a logical approach to address this question."

Table 1: Serum Uric Acid and Risk of CVD

Serum Uric Acid (mg/dL)	Adjusted CVD Risk	P
<3.86	2.68	.148
3.86-4.89	1.35	.68
4.69-5.36	.95	.94
>e;6.38	6.46	.007

Source: Panoulas et al.¹

How Elevated SUA Might Contribute to CVD

• cause endothelial dysfunction
• cause low-grade inflammation
• decrease serum nitric oxide
• activate NF-kappa B and AP-1 transcription factors
• increase expression of COX-2 and thromboxane
• induce production of platelet-derived growth factor and monocyte chemoattractant protein 1 (MCP-1), which can induce smooth muscle proliferation and monocyte/macrophage infiltration

Source: Panoulas et al.¹

Reference